Supplementary Information to Chapter 30

OVERVIEW OF ELECTROLYTE BALANCE

Normal Na, K, Cl
Water balance
Hormones
Dehydration, overhydration, edema
Sodium, increased/decreased
Potassium, increased/decreased

Electrolyte Concentration
Solutes Plasma Interstitial fluid Intracellular fluid
mEq/L (mEq/L) (mEq/L)
Cations:
Sodium 140 146 12
Potassium 4 5 160
Calcium 5 3 –
Magnesium 1.5 1 34
Anions:
Chloride 105 117 2
Bicarbonate 24 27 10
Sulfate 1 1 –
Phosphate 2 2 140
Protein 15 7 54
Other anion 13 1 –

¾¾ Osmotic equilibrium depends on solute particles.

¾¾ Solutes of body fluids
• ­Organic compounds of small molecular weight
• ­Organic compounds of large molecular weight
• ­Electrolytes.
¾¾ Osmolarity
No. of moles/mmoles of solute per liter of solution.
¾¾ Osmolality
No. of moles/mmoles of solute per kgm of solvent
Mainly determined by electrolytes.
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Since, osmolality is dependent on the number of solute particles, the major determinant factor is the sodium.
Therefore, sodium and water balance are dependent on each other and cannot be considered separately.
It is maintained by the kidney, which excretes either water or solute as the case may be.
¾¾ Osmolality
• Plasma—mainly contributed by Na.
• ICF—mainly contributed by K.
• Plasma osmolality
2 × [Na] + 2 × [K] + urea + glucose.
• N value = 285–295 m osmoles/kg.
The difference in measured osmolality and calculated osmolality may increase causing an osmolar gap, when
abnormal compounds such as ethanol, mannitol, neutral and cationic amino acids etc. are present.

Effective Osmolality
It is the term used for those extracellular solutes that determine water movement across the cell membrane. Permeable
solutes such as urea and alcohol enter into the cell and achieve osmotic equilibrium. Although, there is increase in
osmolality, there is no shift in water.
On the other hand, if impermeable solutes such as glucose, mannitol, etc. are present in ECF, water shifts
from intracellular fluid to extracellular fluid and extracellular osmolality is increased.
So, for every 100 mg/dL increase in glucose, 1.5 mmol/L of sodium is reduced (dilutional hyponatremia). Hence, the
plasma sodium is a reliable index of total and effective osmolality in the normal and clinical situations.
Crystalloids and water can easily diffuse across membranes, but an osmotic gradient is provided by the non­diffusible
colloidal (protein) particles.
The colloid osmotic pressure exerted by proteins is the major factor, which maintains the intracellular and intravascular
fluid compartments.
If this gradient is reduced, the fluid will extravasate and accumulate in the interstitial space leading to edema.
 Supplementary Information to Chapter 30 99

Hormones Regulating Water Balance

¾¾ Aldosterone
¾¾ Renin – Angiotensin system
¾¾ ADH
¾¾ ANP

Aldosterone
¾¾ Mineralocorticoid
¾¾ From zona glomerulosa of renal cortex
¾¾ Causes Na+ reabsorption from renal tubules
¾¾ K+ and H+ lost in urine.

Renin/Aldosterone
¾¾ Renin ↑ in response to renal blood flow decrease, decreased tubular Na+ delivery.
¾¾ Increases aldosterone; causes Na+ absorption and, as a result, water absorption.
¾¾ Less potent than ADH or thirst in maintaining normal volume status.
100 Textbook of Biochemistry— Case Studies

ADH (Vasopressin)
¾¾ From posterior pituitary.
¾¾ High plasma osmolality causes stimulation of osmoreceptors of hypothalamus.
¾¾ Causes release of ADH.
¾¾ Increases water reabsorption by DCT and CD of kidneys.

Antidiuretic Hormone
¾¾ 1% rise in osmolality triggers ADH production, which increases renal reabsorption of H2O.
¾¾ Response also affected by volume loss (> 5%); will override signal from low osmolality.
¾¾ Can reduce but not eliminate water losses.

Fluid regulation by ADH

Natriuretic Peptides
¾¾ Polypeptide hormone from right atrium.
¾¾ Stimulated by increased cardiac stretch.
¾¾ Increases sodium loss and, as a result, increases water excretion.
¾¾ Decreases aldosterone production.
¾¾ B-­type natriuretic peptide (BNP) available in prescription form to treat congestive heart failure.

Thirst
¾¾ Most important factor in maintaining normal fluid balance.
¾¾ About 1% increase in osmolality causes thirst.
¾¾ About 5% decrease in volume stimulates thirst.
¾¾ Lack of access to water or poor thirst is the major cause of hypernatremia.
¾¾ Thirst contributes to hyponatremia in fluid loss, edematous states (triggered by low intravascular volume).

Salient features of electrolyte imbalance

1. Hypo-­osmolality and hyponatremia go hand in hand.
2. Hypo-­osmolality causes swelling of cells and hyper­-osmolality causes dehydration of cells.
 Supplementary Information to Chapter 30 101

3. Hyponatremia of ECF causes symptoms when associated with hyperkalemia.

4. Dilutional hyponatremia due to glucose or mannitol increases the effects of hyperosmolity.
5. Fatigue and muscle cramps are the common symptoms of electrolyte depletion.
6. Hypo­osmolality of gastrointestinal cells causes nausea, vomiting and paralytic ileus.

Dehydration
¾¾ Due to loss of water alone
¾¾ Due to loss of water and Na

3 types
¾¾ Isotonic contraction
¾¾ Hypotonic contraction
¾¾ Hypertonic contraction

Isotonic Contraction
¾¾ Cause—Loss of fluid isotonic with plasma
• ­Loss of GI fluid—small intestinal fistula, obstruction, paralytic ileus
• ­Recovery phase of renal failure
• Hypovolemia — ­↓ ed renal blood flow
— ­uremia, oliguria
• Plasma Na normal
• Hypotension in severe cases.

Hypotonic Contraction
¾¾ Due to Na depletion
¾¾ Causes
• ­Infusion of large amounts of IV dextrose
• ­Deficiency of Aldosterone
¾¾ Hypo-osmolality inhibits ADH – Excessive water loss—plasma Na and osmolality restored—hypo-osmolar
contraction.
¾¾ Water depletion without electrolyte loss.
¾¾ Causes –
• ­Diarrhea, vomiting
• ­Diabetes insipidus.
¾¾ ↑ ed Na in plasma — ↑­ ed osmolality
¾¾ ↓ ed renal blood flow — aldosterone secretion — further Na retention and hypertension.
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Treatment
¾¾ Oral supply of water
¾¾ If not possible, IV administration of 5% glucose
¾¾ If electrolytes also lost, oral supplementation or IV saline infusion.

Overhydration (Water intoxication)

¾¾ Due to retention of water
• Isotonic expansion
• Hypotonic expansion
• Hypertonic expansion.

Isotonic Expansion
¾¾ Water and Na retention
¾¾ Causes.
• ­Secondary to hypertension, cardiac failure
• ­secondary hyperaldosteronism
• ­Hypoalbuminemia due to nephrotic syndrome, protein malnutrition.
 Supplementary Information to Chapter 30 103

Hypotonic Expansion
¾¾ Predominant water excess
¾¾ Causes –
• ­Glomerular dysfunction
• ­Increased ADH
¾¾ High ECF volume inhibits aldosterone—hyponatremia and low osmolality persists.

Hypertonic Expansion
¾¾ Retention of Na
¾¾ High plasma osmolality—ADH—osmolality restored
¾¾ High aldosterone causes Na retention
¾¾ Associated Hypokalemia—Metabolic alkalosis
¾¾ Cerebral cellular overhydration—coma, death.

Laboratory Tests of Fluid and Electrolyte Status

¾¾ Serum:
• Sodium
• Potassium
• Chloride
• Osmolality (freezing point depress)
• Urea, Creatinine
¾¾ Urine electrolytes:
• Sodium excretion
• Potassium excretion
¾¾ Hematocrit.

Urea, Creatinine
¾¾ While usually used to indicate renal function, also affected by changes in volume status
¾¾ Volume depletion typically causes increase in Blood urea nitrogen (BUN) and BUN/creatinine ratio
¾¾ Volume overload causes decrease in BUN, creatinine
¾¾ Best compared to patient’s baseline

Urine Electrolytes
¾¾ Useful for determining cause of electrolyte disorder
¾¾ Must interpret in light of volume status, serum K+ of patient
¾¾ Random urine usually adequate by calculating fractional excretion or transtubular potassium gradient (TTKG).

Sodium Excretion
¾¾ In extrarenal sodium loss, > 99.5% reabsorbed.
¾¾ With tubular damage, diuretics, adrenal insufficiency, volume overload, FENa increases, often > 5%
U NA × PCr
FENa = × 100
PNa × U Cr
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Potassium Excretion
¾¾ In extrarenal potassium loss, maximum absorbed is ~ 85­90%
¾¾ Potassium losses best described as transtubular K+ gradient (TTKG)
U K × POsm
TTKG =
PK × U Osm
¾¾ TTKG > 8 = potassium wasting,
< 2 = potassium retention.

Causes of Hypernatremia
1.
Cushing’s disease
2.
Prolonged cortisone therapy
3.
In pregnancy, steroid hormones cause sodium retention in the body
4.
In dehydration, when water is predominantly lost, blood volume is decreased with apparent increased concentration
of sodium
5. Exchange transfusion with stored blood
6. Primary hyperaldosteronism
7. Elderly patients with poor water intake, and inability to express thirst
8. Excessive intake of salt
9. Drugs:
Ampicillin
Tetracycline
Anabolic steroids
Oral contraceptives
Loop diuretics.

Causes of Hyponatremia
1. Vomiting
2. Diarrhea
3. Burns
4. Addison’s disease (adrenal insufficiency)
5. Renal tubular acidosis (tubular reabsorption of sodium is defective)
6. Chronic renal failure, nephrotic syndrome
7. Congestive cardiac failure
8. Hyperglycemia and ketoacidosis
9. Excess non­electrolyte (glucose) IV infusion
10. SIADH and defective ADH secretion
11. Pseudo- o­ r dilutional hyponatremia
Hyperproteinemia (e.g. myeloma)
Mannitol
12. Drugs:
ACE inhibitors, lithium, NSAIDs,
vasopressin and oxytocin Chlorpropamide
 Supplementary Information to Chapter 30 105

Syndrome of Inappropriate Antidiuretic Hormone Secretion

¾¾ Common cause of hyponatremia; leads to inappropriately concentrated urine despite plasma osmolality ↓ and slight
volume ↑.
¾¾ Common causes include:
• Tumors (especially small cell lung cancer)
• Lung disease
• CNS disease
• Medications (especially psychiatric)

Diagnostic criteria for SIADH

a) Hyponatremia (<135 mmol/L)
b) Decreased osmolality (<270 mOsm/kg)
c) Urine sodium >20 mmol/L
d) Urine osmolality >100 mOsm/kg.

Osmotic Shifts
¾¾ Increased level of solutes that don’t cross cell membrane cause movement of water, lowering plasma Na
¾¾ Most commonly due to diabetes
¾¾ Administration of mannitol, absorption of glycine from irrigation fluids (TURP, endometrial ablation) less common
causes
¾¾ Hallmark: Normal or high plasma osmo.

Hyperkalemia
¾¾ In hyperkalemia, there is increased membrane excitability, which leads to ventricular arrythmia and ventricular
fibrillation.
¾¾ Hyperkalemia is characterized by flaccid paralysis, bradycardia and cardiac arrest.
¾¾ ECG shows elevated T wave, widening of QRS complex and lengthening of PR interval.
¾¾ Must first exclude artifactual hyperkalemia:
• Hemolysis
• Delayed separation (especially if refrigerated)
• EDTA contamination
• Fist clenching/relaxing during draw.
¾¾ True hyperkalemia usually due to:
• Decreased excretion (renal insufficiency, hypoaldosteronism)
• Increased intake
• Shift of potassium out of cells
¾¾ Laboratory tests of limited use in determining cause; TTKG < 2 confirms decreased excretion as pathogenetic.
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¾¾ Medications that cause hyperkalemia usually inhibit renin/aldosterone system:

• Renin production: NSAIDS, β-blockers
• ACE inhibitors
• AGII-­receptor blockers
• Heparin (its preservative, chlorbutanol, inhibits aldosterone production)
• Potassium­sparing diuretics.

Release from Cells

¾¾ Occasional cause of hyperkalemia
¾¾ Most commonly due to acidosis, insulin deficiency
¾¾ Less commonly due to cell lysis (hemolytic anemia, rhabdomyolysis, tumor lysis); usually requires decreased renal
excretion as well before hyperkalemia develops.

Redistribution of Serum Potassium
Increases K+ entry into cells leading to hypokalemia Impairs K+ entry into cells or exit of K+ from cells; hyperkalemia
Insulin Glucagon
Beta adrenergic stimuli Alpha adrenergic stimuli
Alkalosis Acidosis
↑ osmolality
↑ catabolism

Hypokalemia
¾¾ True hypokalemia usually due to:
• Increased excretion
• Decreased intake
• Shift of potassium into cells.
¾¾ Laboratory tests of limited use in determining cause; TTKG > 10, confirms increased renal excretion as pathogenetic.

Plasma potassium level is below 3 mmol/L. A value less than 3.5 mmol/L is to be viewed with caution. Mortality and
morbidity are high.
Signs and symptoms: Muscular weakness, fatigue, muscle cramps, hypotension, decreased reflexes, palpitation, cardiac
arrythmias and cardiac arrest.
ECG waves are flattened, T wave is inverted, ST segment is lowered with AV block.
This may be corrected by oral feeding of orange juice.

Causes of Hypokalemia
1. Increased renal excretion
Cushing’s syndrome
Hyperaldosteronism.
2. Shift or redistribution of potassium
Alkalosis
Insulin therapy
Periodic paralysis (abnormal Na-K-ATPase).
 Supplementary Information to Chapter 30 107

3. Gastrointestinal loss
Diarrhea, vomiting, aspiration.
4. Intravenous saline infusion in excess
5. Drugs:
Insulin
Osmotic diuretics
Thiazides, acetazolamide
Corticosteroids.

When Potassium level should be checked?

1. Cardiac diseases
2. Administration of drugs such as diuretics, ACE inhibitors, NSAIDs
3. Diabetic ketoacidosis
4. Receiving large volume of IV fluids
5. Fluid loss (burns, total parenteral nutrition, diarrhea)
6. Renal impairment
7. Weakness of unknown etiology.

Hyperchloremia is seen in:

1. Dehydration
2. Cushing’s syndrome.
Mineralocorticoids cause increased reabsorption from kidney tubules.
3. Severe diarrhea leads to loss of bicarbonate and compensatory retention of chloride.
4. Renal tubular acidosis.

Causes for Hypochloremia

1. Excessive vomiting. HCl is lost, so plasma Cl– is lowered. There will be compensatory increase in plasma bicarbonate.
This is called hypochloremic alkalosis.
2. Excessive sweating.
3. In Addison’s disease, aldosterone is diminished, renal tubular reabsorption of Cl– is decreased, and more Cl– is
excreted.